Pembrolizumab + AR Inhibitors for Prostate Cancer

Recruiting at 3 trial locations

Overseen By GUCLINIC Research Team

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Weill Medical College of Cornell University

Must be taking: LHRH/GnRH analogue

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Autoimmune disease, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 25

76 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a new combination of treatments can more effectively combat prostate cancer. Researchers are testing if adding a drug that targets cancer cells with radiation (225Ac-J591, an alpha-PSMA-targeted radionuclide therapy) to a mix of an immunotherapy drug (pembrolizumab) and hormone therapy (androgen receptor inhibitor or ARI) is more effective than the immunotherapy and hormone therapy alone. The trial targets men with prostate cancer that has spread and continues to grow despite treatment. Those who have previously tried treatments like enzalutamide or abiraterone and have experienced progression might be suitable candidates. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in prostate cancer therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must continue primary androgen deprivation therapy if you haven't had an orchiectomy, and you can stay on bisphosphonates or denosumab if you've been on a stable dose for at least 4 weeks before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that 225Ac-J591 is generally well-tolerated. In one study, many patients experienced a drop in prostate-specific antigen (PSA) levels, a marker used to monitor prostate cancer. Common side effects included fatigue and low blood cell counts.

Androgen receptor inhibitors (ARIs) also treat prostate cancer and can cause side effects such as tiredness, weight gain, and hot flashes. Some studies have noted a higher risk of heart-related issues.

Pembrolizumab has demonstrated general safety. It can cause side effects like fatigue and skin rash but is usually considered safe for many patients.

In summary, each component of this treatment has undergone safety testing in humans. While side effects can occur, they are usually manageable. Always consult a doctor to understand what this means for your health. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for prostate cancer because they bring innovative approaches to combatting the disease. Unlike most standard treatments like hormone therapy or chemotherapy, the combination of Pembrolizumab with 225Ac-J591 and androgen receptor inhibitors (ARIs) uses a targeted radiolabeled antibody, 225Ac-J591, to specifically attack cancer cells. Moreover, Pembrolizumab, an immune checkpoint inhibitor, boosts the body's immune system to fight the cancer, which is not a feature of traditional treatments. This combination has the potential to enhance the effectiveness of ARIs, like enzalutamide, apalutamide, or darolutamide, by not only blocking cancer-promoting signals but also directly targeting and destroying cancer cells.

What evidence suggests that this trial's treatments could be effective against prostate cancer?

Research has shown that pembrolizumab, when combined with enzalutamide (a drug that blocks male hormones), has limited success in treating advanced prostate cancer that no longer responds to standard hormone therapy. This suggests it might not control the cancer effectively on its own. In this trial, one group of participants will receive pembrolizumab and an androgen receptor pathway inhibitor (ARI) like enzalutamide. Another group will receive pembrolizumab, ARI, and 225Ac-J591, a targeted radiation treatment. Adding 225Ac-J591 aims to improve outcomes by delivering radiation directly to prostate cancer cells. Previous studies on similar treatments have suggested that targeting a specific protein on prostate cancer cells with radiation can help slow the cancer's progression. This combination approach is promising because it might enhance the immune system's ability to fight cancer while also directly attacking cancer cells with radiation. ^{6 7 8 9 10}

Who Is on the Research Team?

Scott Tagawa, MD, MS

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

Men over 18 with advanced prostate cancer that's resistant to hormone therapy and has progressed after certain treatments. They must have a good performance status, normal organ function, and agree to contraception during the trial plus 4 months after. Exclusions include other cancers within 2 years, active infections like HIV or hepatitis, recent blood clots or radiotherapy, autoimmune diseases requiring treatment in the last 2 years, current participation in another study drug trial.

Inclusion Criteria

My testosterone levels are below 50 ng/dL, and I am on hormone therapy or have had an orchiectomy.

My blood counts and kidney, liver, and clotting functions are within normal ranges.

My prostate cancer is worsening, shown by rising PSA levels, new bone lesions, or growth in scans.

Exclusion Criteria

I have been on a stable dose of bisphosphonates or denosumab for over 4 weeks.

I haven't needed systemic treatment for an autoimmune disease in the last 2 years.

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment Phase I

Participants receive pembrolizumab, ARPI, and a single dose of 225Ac-J591 to determine the optimal dose

12 weeks

Pembrolizumab every 6 weeks, 1 dose of 225Ac-J591

Safety Follow-up

Safety follow-up to monitor dose-limiting toxicity and determine optimal dose for phase II

12 weeks

Treatment Phase II

Randomized treatment with pembrolizumab and ARPI, with or without 225Ac-J591

Up to 2 years

Pembrolizumab every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 100 months

Imaging every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 225Ac-J591
• Androgen receptor pathway inhibitor
• Pembrolizumab

Trial Overview

The trial is testing if adding a radioactive drug called 225Ac-J591 to pembrolizumab (an immunotherapy) and an ARPI (androgen receptor pathway inhibitor) can better fight prostate cancer than just pembrolizumab + ARPI. It's a phase I/II study which means they're looking at safety and effectiveness.

How Is the Trial Designed?

Group I: Pembrolizumab + ARI Experimental Treatment 3 Interventions

Patients will receive pembrolizumab (400mg every 6 weeks) and ARI (standard dose schedule) without 225Ac-J591.

Group II: Pembrolizumab + 225Ac-J591 + ARI Experimental Treatment 4 Interventions

Patients will receive one dose of 225Ac-J591 (single dose, either 65 or 80 Kbq/kg) in combination with pembrolizumab (400mg every 6 weeks) and ARI (standard dose schedule, examples of ARI include enzalutamide, apalutamide, darolutamide).

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

In a meta-analysis of 6 studies involving 201 patients with metastatic castration-resistant prostate cancer, 225Ac-PSMA-617 demonstrated a high efficacy, with 87% of patients showing any decrease in prostate-specific antigen (PSA) levels and 66% achieving a PSA decrease of more than 50%.

The treatment was found to be relatively safe, with the most common side effect being xerostomia (dry mouth) occurring in 77.1% of patients, but only 3% experiencing severe cases, indicating that 225Ac-PSMA-617 is a promising option with manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of 225Ac-PSMA-617-Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. Ma, J., Li, L., Liao, T., et al.[2022]

In a study of 56 patients with metastatic castration-resistant prostate cancer (mCRPC) who had exhausted standard treatments, [225Ac]Ac-PSMA-617 targeted alpha therapy showed promising efficacy, with 91% of patients experiencing a decline in prostate-specific antigen (PSA) levels, and a median overall survival of 15 months.

The treatment was well-tolerated, with most adverse events being mild to moderate, such as transient fatigue in 70% of patients and xerostomia in about one-third, indicating that [225Ac]Ac-PSMA-617 could be a viable option for patients with advanced mCRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study. Ballal, S., Yadav, MP., Satapathy, S., et al.[2023]

The combination of the androgen receptor inhibitor darolutamide and the PSMA-targeted thorium-227 conjugate (PSMA-TTC) showed synergistic antitumor efficacy in various prostate cancer models, including those resistant to other treatments.

Darolutamide increased the expression of PSMA, leading to enhanced uptake of PSMA-TTC in tumors and greater DNA damage, suggesting a promising new approach for treating prostate cancer that warrants further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models. Hammer, S., Schlicker, A., Zitzmann-Kolbe, S., et al.[2023]

The new α-particle-emitting compound 225Ac-L1 shows specific targeting and effective cell kill in prostate cancer cells that express PSMA, demonstrating significant tumor growth inhibition and improved survival in xenograft models.

While 225Ac-L1 has promising efficacy, it also presents some off-target radiotoxicity, particularly in the kidneys and liver, with a maximum tolerated dose estimated at about 1 MBq/kg, indicating a need for careful dosing in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of 213Bi- and 225Ac-Labeled Low-Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer. Banerjee, SR., Lisok, A., Minn, I., et al.[2022]

In a phase II trial involving men with metastatic, castration-resistant prostate cancer, Lutetium-177 PSMA-617 was shown to extend survival and enhance quality of life for patients whose disease progressed despite standard treatments.

This study highlights the potential of targeted radionuclide therapy as an effective option for patients with advanced prostate cancer, suggesting a promising new avenue for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radionuclide Treatment Yields Responses in mCRPC. [2020]

In the ALSYMPCA trial involving 600 patients treated with radium-223, the treatment was found to be well tolerated with a low incidence of myelosuppression and no new safety concerns reported up to 3 years after the first injection.

While 94% of radium-223 patients experienced treatment-emergent adverse events, serious hematologic issues were rare, and long-term follow-up showed no cases of acute myelogenous leukemia or myelodysplastic syndrome, indicating a favorable safety profile for radium-223 in treating symptomatic prostate cancer with bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. Parker, CC., Coleman, RE., Sartor, O., et al.[2022]

The study of 32 patients with metastatic castration-resistant prostate cancer (mCRPC) showed that the radiolabeled antibody 225Ac-J591 is safe, with a maximum tolerated dose not reached and only one patient experiencing dose-limiting toxicity.

Preliminary efficacy results indicated that 46.9% of patients had at least a 50% decline in prostate-specific antigen (PSA) levels, and 59.1% showed a response in circulating tumor cell counts, suggesting potential effectiveness of this novel therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591. Tagawa, ST., Thomas, C., Sartor, AO., et al.[2023]

In a study involving mouse models and a patient with castration-sensitive prostate cancer, androgen receptor (AR) inhibition significantly increased prostate-specific membrane antigen (PSMA) uptake, suggesting enhanced imaging of cancer lesions.

After treatment with androgen deprivation therapy (ADT), the patient showed a 7-fold increase in PSMA uptake, with many lesions only becoming visible post-treatment, indicating that AR inhibition may improve both diagnosis and treatment of prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

68Ga-PSMA-11 PET Imaging of Response to Androgen Receptor Inhibition: First Human Experience. Hope, TA., Truillet, C., Ehman, EC., et al.[2021]

In a phase 3 trial involving 831 patients with metastatic castration-resistant prostate cancer, the addition of [177Lu]Lu-PSMA-617 to standard care significantly delayed the time to first symptomatic skeletal event, with a median of 11.5 months compared to 6.8 months for standard care alone.

Patients receiving [177Lu]Lu-PSMA-617 also reported improved health-related quality of life and less pain, although there were some serious adverse events, including hematological issues, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life and pain outcomes with [177Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION): a multicentre, open-label, randomised, phase 3 trial. Fizazi, K., Herrmann, K., Krause, BJ., et al.[2023]

Targeted alpha therapy using 225Ac-labeled PSMA-617 has shown remarkable therapeutic efficacy in treating metastatic castration-resistant prostate cancer, highlighting its potential as a treatment option.

The review also discusses the production methods for 225Ac and its daughter nuclide 213Bi, along with clinical experiences in using these alpha emitters for various cancers, including bladder cancer and brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Overview of Targeted Alpha Therapy with 225Actinium and 213Bismuth. Morgenstern, A., Apostolidis, C., Kratochwil, C., et al.[2019]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04946370

NCT04946370 | Phase I/II Trial of Pembrolizumab and ...

This study will assess whether 225Ac-J591 + pembrolizumab + androgen receptor inhibitor (ARI) is more effective against prostate cancer than pembrolizumab + ARI ...

2.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/37940446/

Cohort C of the Phase 1b/2 KEYNOTE-365 Study

Pembrolizumab plus enzalutamide showed limited antitumor activity and manageable safety in patients with metastatic castration-resistant prostate cancer.

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02861573

NCT02861573 | Study of Pembrolizumab (MK-3475) ...

The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combination therapy in participants with metastatic castration ...

4.

theranostictrials.org

theranostictrials.org/studies/cl74bp9il0233ajjfrlrlvs3d

Prostate (GU)

PSMA-directed Targeted Alpha Therapy With 225Ac-PSMA-I&T of Castration-resISTant Prostate Cancer (TATCIST). A Phase II Clinical Trial.

5.

fredhutch.org

fredhutch.org/en/research/clinical-trials/trial-details.fh_trial_id_11837.study-of-pembrolizumab-mk-3475-combination-therapies-in-metastatic-castration-resistant-prostate-cancer-mk-3475-365-keynote-365.html

Study of Pembrolizumab (MK-3475) Combination ...

The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combination therapy in patients with metastatic castrate resistant ...

6.

urotoday.com

urotoday.com/conference-highlights/aua-2025/aua-2025-prostate-cancer/160028-aua-2025-225ac-j591-psma-targeted-radionuclide-therapy-in-metastatic-castration-resistant-prostate-cancer-patients-with-prior-177lu-psma-therapy.html

AUA 2025: 225Ac-J591 PSMA-Targeted Radionuclide ...

Dr. Abdul Baseet Arham presented an analysis of the efficacy and safety of 225Ac-J591 PSMA-targeted radionuclide therapy in metastatic castrate-resistant ...

7.

auajournals.org

auajournals.org/doi/10.1097/01.JU.0001109880.25183.6b.06

PD13-06 225Ac-J591 PSMA-TARGETED RADIONUCLIDE ...

CONCLUSIONS: PSMA-targeted alpha radionuclide therapy using 225Ac-J591 has efficacy in patients with mCRPC despite prior 177Lu-PSMA. Common ...

8.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.185

Mature phase 1 follow up of alpha emitter 225Ac-J591 with ...

The RP2D of 225Ac-J591 was 35 KGBq/kg. 17 (94%) patients experienced a decline in PSA levels, with 11 out of 17 (64%) achieving PSA50 response.

9.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/37922438/

A Phase I Dose-Escalation Study of 225Ac-J591 - PubMed - NIH

This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, ...

10.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04576871

NCT04576871 | Re-treatment 225Ac-J591 for mCRPC

This is an open-label, pilot study designed to determine the safety of PSMA-TRT re-treatment with 225Ac-J591, which will be given in a single dose on D1, ...